chr17-42980646-G-A

Variant names:

• chr17-42980646-G-A
• rs1037379804
• NM_173079.5:c.70G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_173079.5(RUNDC1):​c.70G>A​(p.Glu24Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000897 in 1,448,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000090 (0 hom.)
• Consequence: RUNDC1 NM_173079.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.01
• Publications: 0 publications found

Genes affected

RUNDC1 (HGNC:25418): (RUN domain containing 1) This gene encodes a protein that contains a RUN (RPIP8, UNC-14 and NESCA) domain and a coiled coil domain. The encoded protein may negatively regulate p53 transcriptional activity. This gene is a potential candidate gene for predisposition to glioma in humans. [provided by RefSeq, May 2017]

PTGES3L-AARSD1 (HGNC:43946): (PTGES3L-AARSD1 readthrough) This locus represents naturally occurring readthrough transcription between the neighboring PTGES3L (prostaglandin E synthase 3 (cytosolic)-like) and AARSD1(alanyl-tRNA synthetase domain containing 1) genes on chromosome 17. The readthrough transcript encodes a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, May 2012]

PTGES3L (HGNC:43943): (prostaglandin E synthase 3 like) Predicted to enable Hsp90 protein binding activity and chaperone binding activity. Predicted to be involved in chaperone-mediated protein complex assembly and protein folding. Predicted to be active in cytosol and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08578554).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNDC1	NM_173079.5	c.70G>A	p.Glu24Lys	missense_variant	Exon 1 of 5	ENST00000361677.6	NP_775102.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNDC1	ENST00000361677.6	c.70G>A	p.Glu24Lys	missense_variant	Exon 1 of 5	1	NM_173079.5	ENSP00000354622.1
PTGES3L-AARSD1	ENST00000421990.7	c.-593C>T		upstream_gene_variant		2		ENSP00000409924.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000457 AC: 1 AN: 218942 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000103

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000897 AC: 13 AN: 1448654 Hom.: 0 Cov.: 75 AF XY: 0.00000973 AC XY: 7 AN XY: 719768

African (AFR) AF: 0.00 AC: 0 AN: 33316

American (AMR) AF: 0.00 AC: 0 AN: 42446

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25736

East Asian (EAS) AF: 0.00 AC: 0 AN: 39330

South Asian (SAS) AF: 0.00 AC: 0 AN: 84346

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51428

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1108142

Other (OTH) AF: 0.00 AC: 0 AN: 59774

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000313 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.70G>A (p.E24K) alteration is located in exon 1 (coding exon 1) of the RUNDC1 gene. This alteration results from a G to A substitution at nucleotide position 70, causing the glutamic acid (E) at amino acid position 24 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.086	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.0
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.10
Sift	Benign	0.50	T
Sift4G	Benign	0.56	T
Polyphen		0.0020	B
Vest4		0.31
MutPred		0.14		Gain of ubiquitination at E24 (P = 0.0082);
MVP		0.29
MPC		0.47
ClinPred		0.33	T
GERP RS		4.1
PromoterAI		0.046	Neutral
Varity_R		0.15
gMVP		0.50
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1037379804; hg19: chr17-41132663;